Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration

Willayat Yousuf Wani, Ramesh J L Kandimalla, Deep Raj Sharma, Alka Kaushal, Anand Ruban, Aditya Sunkaria, Jayalakshmi Vallamkondu, Alberto Chiarugi, P (Hemachandra) Reddy, Kiran Dip Gill

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G0/G1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.

Original languageEnglish (US)
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
DOIs
StateAccepted/In press - Mar 13 2016
Externally publishedYes

Keywords

  • Cyclin-D1
  • Dichlorvos
  • Neurodegeneration
  • Oxidative stress
  • P21

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

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  • Cite this

    Wani, W. Y., Kandimalla, R. J. L., Sharma, D. R., Kaushal, A., Ruban, A., Sunkaria, A., Vallamkondu, J., Chiarugi, A., Reddy, P. H., & Gill, K. D. (Accepted/In press). Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration. Biochimica et Biophysica Acta - Molecular Basis of Disease. https://doi.org/10.1016/j.bbadis.2016.05.014